Every day over 6800 new infections take place and 5700 persons die from Human immunodeficiency virus infections (HIV/AIDS) worldwide, mostly because of inadequate access to HIV prevention and treatment services. Women who acquired HIV-1 through vaginal intercourse represent <60% of new infections in Africa. Still today, there is no known cure for the condition. Thus, there is a critical and urgent need for effective control methods and strategies to prevent the continuous spread of HIV/AIDS and break the cycle of the new HIV infections. Although an HIV vaccine would be the most suitable prevention strategy, an effective or even partially effective vaccine candidate has yet to be identified. Thus the development of a topical microbicide which can be used, unlike condoms, by women without the knowledge of their partner would provide a major benefit for slowing the global spread of HIV-1. Ideally a successful microbicide delivery system will have to (i) protect mucosal surfaces at risk of HIV-1 transmission, (ii) prevent the dissemination of infected cells from the local mucosa to the regional lymph nodes and, (iii) provide a controlled release of the microbicide to ensure long lasting protecting effect, (iv) be stimuli-sensitive to maximize the drug efficacy and provide required preventive dose on demand. The currently use of gel-based systems do not meet all these requirements. Thus nanosized drug carriers or drug loaded nanocarriers (NC) appear as promising alternative. Our long term goal is to identify novel multifunctional nanocarriers for controlled delivery of the microbicide either for prevention or treatment of HIV/AIDS. The objective of this proposal is to use nanocarrier for the controlled delivery of a model topical microbicide (Tenofovir). We have recently prepared several bioactive agents loaded chitosan and polyester nanocarrier with particle diameter ranging from <100 nm to <1000 nm. The central hypothesis is that a topical microbicide loaded nanocarrier is safer and more effective than the native drug in HIV/AIDS prevention. We will test this hypothesis with the following three specific aims. Specific aim#1: To develop a microbicide loaded bioadhesive nanocarrier for topical delivery in order to enhance the drug local duration of action. Specific aim#2: To develop a microbicide loaded pH sensitive nanocarrier for topical delivery in order to take advantage of the pH increase during intercourse to trigger effective drug dose release for an enhanced action. Specific aim#3: To develop a microbicide loaded functionalized nanocarrier with cell penetrating ligands in order to prevent the dissemination of the virus from the local mucosa to the regional lymph nodes. In each aim in order to identify optimal NC, we will thoroughly characterize the developed NC physico-chemically, assess their safety by MTT and Lactobacillus toxicity assay, test their efficacy in vitro (with seminal plasma, human PBMC-based and cervical explants assays) and elucidate their intracellular trafficking mechanism. It is anticipated that this innovative approach will lead to the identification of NC as a safer and more effective alternative to current microbicide delivery systems in HIV/AIDS prevention. PUBLIC HEALTH RELEVANCE: Our long-term goal is to thoroughly identify and characterize a novel microbicide nanocarrier system to improve the safety and efficacy in the prevention of HIV/AIDS transmission process. Specifically, the objective of this application is to develop tenofovir (a model microbicide) loaded nanocarriers that may be made of either bioadhesive (for longer topical duration of action), pH-sensitive (for a triggered release by semen either pH) or functionalized solid lipid matrix (for deeper penetration across the potential path of HIV virus) for prevent the dissemination of the virus. It is anticipated that knowledge gained from this work may be applicable to other microbicides and to other sexually transmitted diseases or human diseases.